Elimination reactions in pharmacy: part two

Here is another example of elimination in pharmacy.

Curare is a type of drug called a muscle relaxant. It acts by blocking nerve impulses at the neuromuscular junction thus causing the muscle to relax. Such drugs are very useful during surgery when the patient needs to be immobilised. The downside to curare is that it takes a long time for the effect to wear off after surgery and can cause respiratory depression. The effect would only wear off after the drug gets metabolised – that is it gets changed in the body – to a not active form. (Metabolism is a process where a drug is changed to another form when it enters our body).

Curare is a drug used to relax the muscles during a surgery. Its effect is slow to wear off after surgery
and may cause inconvenience such as breathing suppression.

Newer muscle relaxants such as atracurium have been developed that has a built-in functional group that allows the drug to rapidly metabolised or changed into an inactive form. One such change involves an elimination reaction of the quarternary ammonium group of the drug

(Refer to notes on elimination of amines).

Elimination reactions in pharmacy: part one

Besides understanding basic principles of a reaction like the mechanisms and how to apply them to solve problems, perhaps you would appreciate an organic reaction better if I present some real-life situations especially related to pharmacy which involve elimination reactions.

The first example is elimination in the synthesis of a well known drug tamoxifen. Tamoxifen is an anti-estrogen antagonist which is used to treat breast cancer that is estrogen receptor positive. It works by binding to the estrogen receptor on the cancer cells thus stopping the uncontrolled cell growth fuelled by estrogen activity.

Tamoxifen tablet 20 mg (Nolvadex is the brand name)

A 3-D structure of tamoxifen

Here is how tamoxifen is originally made:

First, the main skeleton of tamoxifen is made by addition of a Grignard reagent, phenyl magnesium bromide (PhMgBr) which is a good nucleophile to the ketone group. This produces a tertiary alcohol. This tertiary alcohol is then treated with sulfuric acid. Here a dehydration happens. It is an E1 elimination as a carbocation is formed (favoured by it being tertiary and benzylic at the same time).

The freely rotating bond (coloured green) allows the three substituents at the carbon (blue) adjacent to the positively charged one to change positions like this:

So in an E1 elimination like this, there is no stereocontrol (stereospecificity). As the proton (coloured red) gets removed, a mixture of E- and Z-isomers are produced.

This method to make tamoxifen is apparently not satisfactory because we can’t get purely tamoxifen. There are better, improved ways to produce pure tamoxifen. Check out this website: http://www.ch.ic.ac.uk/local/projects/h_tanner/introsynth.html

Drawing reaction mechanisms with curved arrows

A reaction mechanism is a detailed step-by-step description of how reactants are converted to products. It consists of a sequence of steps showing the making of bonds and the breaking of bonds. It is a way to explain or rationalize how a reaction happens to change a reactant to a product.

When bonds are made or broken, there are movements of electrons from one molecule or a group of atoms to another.

In most reactions you meet in organic chemistry (except radical reactions), the electrons move in a pair (two). We draw the flow of this pair of electrons as a curved arrow like this:

Another important point to note is that these two electrons always move from a place of more electrons (or negatively charged) to a place with less electrons (positively charged):

Here are some common examples, which you meet in reactions you have learned:

Whichever a reaction may be, when drawing a mechanism, remember that a curved arrow means the flow of two electrons, and the electrons always flow from a place of more electrons to a place of less electrons, never the opposite direction.

Elimination reaction in a nutshell

Dear Students,

In this three-hour class, I will introduce you to another important reaction: 
Elimination.

In the previous lectures, you have seen alkyl halides undergoing nucleophilic 
substitutions (SN), for example:

The reason is that halogens are very good leaving groups. A nucleophile attacks
 the carbon to which the halogen is attached causing the halogen to leave.


An elimination reaction works quite similarly, like this: 

The halogen leaves but also a hydrogen is taken away. The hydrogen is taken away by a base. The result is the formation of an alkene, or double bond.


You will see more examples like this in my lecture. In this class, you will learn about:
-  the two mechanisms of elimination, E1, and E2
-  Stereochemistry of elimination particularly E2
-  Elimination of cyclic alkyl halides
-  Alcohols and amines can also be made to undergo eliminations


Notes for this lesson are availble for download here:
http://bit.ly/18s3joz

Tutorial questions for this topic are available here:
http://bit.ly/H1iRFH


See you in class.